The present invention relates to a new class of anti-tumor agents based on a new active compound isolated from a sponge.
In connection with our long-standing interest in the chemistry and bioactivity of marine sponges, we found that extracts of the Indo-Pacific sponge Haliclona tulearensis (class Demospongiae, order Haplosclerida, family Chalinidae, genus Haliciona), collected in Sodwana Bay, Durban, South Africa, were quite cytotoxic. Many interesting N-containing metabolites came out from the genus Haliclona1-6. Recently, we reported the isolation of haliclorensin (1), a new N-(3xe2x80x2-arninopropyl)-3-methylazacyclodecane, from H. tulearensis7 of the following formula (A): 
We have now discovered a new N-containing metabolite named halitulin with cytotoxic activity, which in turn has led us to a new class of active compounds.
According to the present invention, there is provided a compound of the general formula (I): 
and related derivatives.
In particular, the present invention provides compounds of the given formula (I) wherein R is selected from:
a) a cycloamino-N-alkylene group of formula (II): 
where m is typically 1 to 6, especially 3, and n is typically 3 to 20, especially 9, and which may be substituted on the ring, for example with one or more C1-C6 alkyl groups, especially with one methyl group xcex2 to the ring nitrogen;
b) a similar cycloaliphatic-alkylene group lacking the ring nitrogen;
c) an optionally substituted alkyl group, cycloalkyl group, aryl group, alkyl group or any other substituent group which does not undermine the activity of the compound, for example an aininoalkylene group of formula xe2x80x94(CH2)pNR1R2, where p is typically 1 to 6, especially 3, and R1 and R2 are hydrogen, aryl or aralkyl;
d) hydrogen.
The nature of the group R is not critical.
Moreover, there can be one or more substituents on the quinoline rings, for example alkyl groups at one or more of the 2-, 3- and 4-positions of one or both quinoline rings.
The present invention further extends to related derivatives of the compounds of formula (I), which include:
a) derivatives of the phenolic hyrioxy groups, such as ethers or esters;
b) oxidised forms such as N-oxides and o-quinolinoquinones;
c) pharmaceutical acceptable acid addition salts
In particular, we provide the compound halitulin of formula: 
Halitulin, a substituted pyrrole, can be isolated from the sponge Haticlona tulearensis, and can be characterised by the following data:
[xcex1]D+7.5xc2x0; (c=2.8, MeOH)
IR xcex4max 3000-3400, 1623, 1597 cmxe2x88x921 
xcexmax(MeOH): 212 (29200), 252 (31600), 364 (4400);
and other data given later.
Over 250 pyrrole-containing compounds are known from marine organisms. A few that resemble the structure of halitulin are polycitone A, polycitrins A and B8, the lamellarins9 from ascidians and the storiamides10 and arcynibins11 from sponges. Halitulin, to the best of our knowledge, is the first natural compound to be discovered that embodies a 7,8-dihydroxyquinoline system. A very few other dihydroxyquinoline-containing compounds are known e.g. luzopeptin, a terrestrial Actinomadura antimicrobial metabolite20 and the marine sponge Verongia aerophoba metabolite 3,4-dihydroxyquinoline-2-carboxylic acid21.
Halitutin (2) was found to have cytotoxic activity. The activity, IC50 values, against cell cultures of P-388 murine leukemia, A-549 human lung carcinoma, HT-29 human colon carcinoma and MEL-28 human melanoma is 0.025, 0.012, 0.012 and 0.025 xcexcg/ml respectively.
We know that the compound haliclorensin is inactive. From this knowledge, we can predict the activity in the compounds of the present invention.
The present invention also relates to pharmaceutical preparations which contain as active ingredient a compound of this invention, as well as processes for preparation. Methods of administration to patients are also envisaged.
Examples of pharmaceutical compositions include any solid (tablets, pills, capsules, granules, etc.) or liquid (solutions, suspensions or emulsions) with suitable composition of oral, topical or parental administration, and they may contain the pure compound or in combination with any carrier or other pharmacologically active compounds. These compositions may need to be sterile when administered parenterally,
The correct dosage of a pharmaceutical composition comprising a compound of this invention will vary according to the pharmaceutical formulation, the mode of application, and the particular situs, host and tumor being treated. Other factors like age, body weight, sex, diet, time of administration, rate of excretion, condition of the host, drug combinations, reaction sensitivities and severity of the disease shall be taken into account. Administration can be carried out continuously or periodically within the maximum tolerated dose.
The compounds may be provided in the pharmaceutical compositions of this intention in the form of a prodrug or precursor, which upon administration converts or is metabolised to the active compound.
The compositions of this invention may be used with other drugs to provide a combination therapy. The other drugs may form part of the same composition, or be provided as a separate composition for administration at the same time or a different time. The identity of the other drug is not particularly limited, and suitable candidates include:
drugs with antimitotic effects, especially those which target cytoskeletal elements, including microtubule modulators such as taxane drugs (such as taxol, paclitaxel, taxotere, docetaxel), podophylotoxins or vinca alkaloids (vincristine, vinblastine);
antimetabolite drugs such as 5-fluorouracil, eytarabine, gemcitabine, purine analogues such as pentostatin, methotrexate);
alkylating agents such as nutrogen mustards (such as cyclophospharnide or ifosphamide);
drugs which target DNA such as the anitracycline drugs adriamycin, doxorubicin, phannorubicin or epirubicin;
drugs which target topoisomerases such as etoposide;
hormones and hormone agonists or antagonists such as estrogens, antiestrogens (tamoxifen and related compounds) and androgens, flutamide, leuprorelin, goserelin, cyprotrone or octreotide;
drugs which target signal transduction in tumour cells including antibody derivatives such as herceptin;
alkylating drugs such as platinum drugs (cisplatin, carboplatin, oxaliplatin, paraplatin) or nitrosoureas;
drugs potentially affecting metastasis of tumours such as matrix metalloproteinase inhibitors;
gene therapy and antisense agents;
antibody therapeutics; and
other bioactive compounds of marine origin, notably the ecteinascidins such as ET-743, or the didemnins such as aplidine.